Technical Field
The present invention relates to pharmaceutical compositions for treating a disorder caused by at least one of lipid metabolism disorders and autophagy dysfunctions, which include a polyrotaxane, and to novel polyrotaxanes.
Background Art
Disorders in which lipids, sugar, cholesterol etc. are accumulated in lysosomes due to genetic deficiency or genetic mutation of membrane transport proteins or catabolic enzymes in lysosomes are collectively called as lysosomal diseases. About 30 types of lysosomal diseases have been designated as specified diseases in Japan, and it has been known that few effective remedies are available.
In Niemann-Pick Type C (hereinafter, sometimes referred to as “NPC disease”) which is one of the lysosomal diseases, for example, cholesterol and lipids are accumulated in lysosomes due to mutation of NPC1 which is a membrane protein. The NPC disease develops from childhood, manifesting symptoms such as progressive neurological dysfunction and hepatosplenomegaly, and is an intractable metabolic disorder causing death at around age of 10 in many cases.
In recent years, use of cyclodextrins has been held as a promising remedy for the NPC disease. Cyclodextrins are cyclic sugars, and are named, depending on the number of repetitions of sugar, as α-cyclodextrin (number of repetitions: 6), β-cyclodextrin (number of repetitions: 7), and γ-cyclodextrin (number of repetitions: 8). These cyclodextrins are known to include various compounds in the cavity, and particularly, β-cyclodextrin is known to have a superior ability to include cholesterol (for example, refer to Non-Patent Literature 1). In recent years, it has been revealed that the amount of cholesterol in cells decreases by allowing β-cyclodextrin modified by hydroxypropyl groups (hereinafter, sometimes referred to as “HP-β-CD”) to act on NPC disease patient-derived cells. Furthermore, it has been discovered that administering HP-β-CD to Npc1-deficient mice (Npc1−/− mice) decreases the amount of cholesterol accumulated in each tissue, and extends the survival (for example, refer to Non-Patent Literature 2). Thus, β-cyclodextrin, which is capable of decreasing the cholesterol accumulated in cells, has been attracting attention as a novel remedy for the NPC disease. Particularly, compassionate use being approved in the United States, and phase I trial of a remedy for the NPC disease being started from the year 2012, it has been considered to be a medicine having an extremely high degree of expectations.
On the other hand, cyclodextrins (hereinafter, sometimes referred to as “CD”), being a low-molecular compound with a molecular weight of about 1,000, have a short blood half-life of about a few tens of minutes, and have problems such as rapid renal excretion immediately after administering, and low cell membrane permeability (for example, refer to Non-Patent Literature 3). Therefore, to have a sufficient therapeutic effect, it is necessary to administer repetitively a highly concentrated CD (the amount administered to the Npc1-deficient mice was 4,000 mg/kg; for example, refer to Non-Patent Literature 2). However, since highly concentrated CD shows hemolytic activity and causes tissue damage, use of highly concentrated CD is a matter of concern due to side effects such as a damage to normal tissues (for example, refer to Non-Patent Literature 4). Therefore, achieving a sufficient therapeutic effect non-invasively on human beings is considered to be difficult.
Consequently, in the present circumstances, a rapid development of a pharmaceutical composition with a high safety, having a superior cholesterol removing effect, and having a high therapeutic effect or a preventive effect on lysosomal diseases including Niemann-Pick Type C, is eagerly sought.
Moreover, it has been revealed in recent years that the lysosomal diseases are not only metabolism disorders of lipids, but are disorders of autophagy which plays a role in protein degradation in cells (for example, refer to Non-Patent Literature 5). In autophagy, organelles such as mitochondria and proteins which have become unnecessary in cells are degraded by lysosomes, but the abnormality in the autophagy function leads to accumulation of unnecessary proteins in cells. It has also been indicated that the disordered function of autophagy is associated with the pathology of lysosomal diseases. Particularly, in NPC disease, it has been shown that autophagosomes accumulate in the cytoplasm (for example, refer to Non-Patent Literature 6). Such an accumulation of autophagosomes indicates that the unnecessary proteins and organelles, which should have been degraded by lysosomes normally, are accumulated in the cytoplasm.
Moreover, as other disorders which show impaired proteolysis in autophagy, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease have been identified (for example, refer to Non-Patent Literature 7).
Consequently, in the present circumstances, a rapid development of a pharmaceutical composition having a high therapeutic effect or preventive effect on disorders caused due to the autophagy dysfunction, including lysosomal diseases, is also eagerly sought.